Abstract This application is for an AD/ADRD supplement (NOT-AG-18-008) to the funded NIH Director?s New Innovator Award (DP2GM119131). Bryostatin (bryostatin I) is one of the few therapeutics to have reached clinical trials for Alzheimer?s disease and related dementias (ADRD). The molecular target of bryostatin is protein kinase C (PKC), a family of over a dozen isoenzymes. The downstream pathways of the alpha and epsilon isoforms (PKC??, PKC???have been implicated in neurogenesis and retention of memory functions, and are therefore relevant to developing treatments for Alzheimer?s disease. Phase IIa clinical trials of bryostatin to treat AD have been completed, and show improvements in mental capacity and memory in patients receiving bryostatin compared to placebo. Despite the adoption of bryostatin as a leading therapeutic to treat ADRD, the structure of the bryostatin-PKC complex has not yet been determined. Detailed knowledge of the molecular interactions between bryostatin and residues within the binding pocket of PKC? and PKC? will provide a structural basis for rational design of bryostatin analogs. Such analogs of the natural product will provide an avenue to improve efficacy and reduce toxicity, widening the therapeutic window for treatments of ADRD. We will employ dynamic nuclear polarization (DNP) enhanced solid state NMR to determine structures of bryostatin bound to the regulatory domains of both PKC? and PKC??